Project Summary: The broad research objective of the proposed project is to investigate the relationship between internalizing symptoms and alcohol problems. Specifically, this will entail an analysis of the genetic and environmental liability shared across traits and an effort to identify genetic variants influencing this association. One component of the project will address these goals through the use of genetic epidemiology. By studying the relationship between these traits in a population of twins, it is possible to partition variance into that which is attributable to genetic versus environmental factors. Using measures of internalizing symptoms (across multiple disorders) and alcohol problems, the research described in this proposal will address questions about the degree to which shared latent genetic liability influences the association between these traits, and whether that shared liability is specific to particular manifestations of internalizing (such as symptoms of major depression, or symptoms of social phobia) or is common across internalizing phenotypes. The second component of the project builds on results from the twin component. Using information about the structure of genetic influences common to internalizing symptoms and alcohol misuse, a single quantitative phenotype will be constructed that approximates an individual's genetic liability to overlap between internalizing and alcohol problems. This phenotype will be used as the dependent variable in a genome-wide association study, with the goal of identifying genetic variants associated with the composite phenotype. PUBLIC HEALTH RELEVANCE: Project Narrative: Research initiatives of the NIAAA include delineation of genetic and behavioral vulnerability to alcohol use and disorders. The proposed project will improve understanding of the latent and specific genetic influences on an internalizing pathway to alcohol use. This information can be used to guide treatment and prevention of both internalizing disorders and alcohol use disorders.